Clinical Perspective of Antimicrobial Resistance in Bacteria

Figures & data

Box 1 MDR, XDR and PDR

The standardized international terminology to describe acquired resistance was established in the 21st century. Multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) are created for public health use and epidemiological purposes to cover the acquired resistance spectrum of AMR bacteria, including Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp. MDR was defined as “acquired non-susceptibility to at least one agent in three or more antimicrobial categories”, XDR was defined as “non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (ie bacterial isolates remain susceptible to only one or two categories) ” and PDR as “non-susceptibility to all agents in all antimicrobial categories”. To interpret an in-vitro antimicrobial susceptibility test results is to identify a MDR strain. When the test shows “resistance to multiple antimicrobial agents, classes or subclasses of antimicrobial agents”, it proves to be a MDR strain which means it is “resistant to one key antimicrobial agent”. For XDR, the first understanding is based on the number of antimicrobials or classes or subclasses to which a bacterium is resistant, and the second one is whether they are “resistant to one or more key antimicrobial agents”. As for PDR, it demonstrates a complete drug-resistance to all routine antibiotics clinically.^Citation1

Table 1 Antimicrobial Resistant Mechanisms of Acinetobacter Baumannii and Pseudomonas Aeruginosa

Resistant Mechanism	Type	Relevant Genes	References
Enzymatic drug inactivation	ESBLs^Citation37	blaTEM, blaSHV, blaCTX-M, blaOXA and other genes
	MBLs^Citation63	blaIMP, blaVIM, blaSIM, blaNDM, blaSPM, blaGIM, blaDIM, intI 1, intI 2
	OXAs	blaOXA-23-like, blaOXA-40/24-like, blaOXA-51-like, blaOXA-58-like, blaOXA-143-like	[64]
	AMEs	aadA1, aph(3′)‐IIb, aph(3′)‐I, aph(6)‐Id, aac(3)‐Id	[37,65]
	16S-RNA methylase	armA, rmtA, rmtB, rmtC, rmtD, rmtE, rmtF, rmtG, rmtH, npmA	[66]
	tetracycline destructases	tetX	[67,68]
Drug target alteration	fluoroquinolone resistance	gyrA/B, parC/E	[69]
	polymyxin resistance	pmrA/pmrB/ mcr-1/lpxA/lpxC/lpxD	[70–72]
Permeability defects	tigecycline resistance	abrp	[73]
Efflux pumps	MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXY-OprM		[74,75]
	Ade	adeA, adeB, adeC, adeRS, adeIJK, abeM	[68]
	QepA, OqxA		[41]

Abbreviations: ESBLs, extended-spectrum β-lactamases; MBLs, metallo-β- lactamases; OXAs, oxacillinases; AMEs, aminoglycoside-modifying enzymes; Ade, Acinetobacter drug efflux.

Table 2 The Percentage of Prevalent Antimicrobial Resistant Bacteria from 9 Countries on 6 Continents

Continent	Country	Year	MRSA	VRE (Faecalis)	VRE (Faecium)	PRSP	CRkp	MDR-PA	MDR-AB	reference
Oceania	Australia	2017	19.0%	1.0%	50.0%	NF	1.0%	NF	NF	[48]
South America	Argentina	2017	45.0%	4.0%	69.0%	15.0%	20.0%	NF	NF	[43]
North America	USA	2016	NF	5.0%	68.0%	17.0%	3.0%	21.0%	NF	[23,51,52]
	Canada	2017	16.0%	NF	NF	16.5%	2.0%	21.0%	NF	[44]
Europe	UK	2019	6.0%	1.6%	22.2%	1.4%	0.7%	2.9%	1.2%	[23,45]
Asia	China	2019	32.2%	0.0%	1.4%	2.7%	6.4%	20.7%	56.1%	[23,50]
	India	2018	39.0%	7.0%	27.0%	3.0%	59.0%	NF	NF	[49]
	Japan	2017	41.0%	NF	NF	1.0%	0.0%	NF	NF	[43]
Africa	South Africa	2016	27.0%	1.0%	5.0%	NF	7.0%	NF	NF	[69]

Notes: NF, not found; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant Enterococcus; PRSP, penicillin-resistant Streptococcus pneumoniae; CRkp, carbapenemase-resistant Enterobacteriaceae; MDR-PA, multidrug-resistant Pseudomonas aeruginosa; MDR-AB, multidrug-resistant Acinetobacter baumannii.

Table 3 Major Antibiotic Resistance Mechanisms, Detection Methods and Medical Recommendations for Popular Antimicrobial Resistance Genes of Antimicrobial Resistant Bacteria

	Popular Antimicrobial Resistance Genes	Major Antibiotic Resistance Mechanisms	Detection Methods	Medication Recommendation
Methicillin-resistant Staphylococcus aureus^Citation77	mecA	Drug target alteration	MIC determination, disk diffusion tests or latex agglutination to detect PBP2a, genotypically using PCR	Vancomycin, linezolid, teicoplanin, daptomycin, sulfamethoxazole/ trimethoprim (SMZ/TMP)
	mecB
	mecC
	mecD
Vancomycin-resistant Enterococcus^Citation18	vanA	Drug target alteration	MIC determination, disk diffusion, the breakpoint agar method, PCR-based methods, DNA microarray-based	Linezolid, nitrofurantoin, fosfomycin (urinary tract infection)
	vanB
	vanC
	vanD/E/F/G/L/M/N
Penicillin-resistant Streptococcus pneumoniae^Citation20	pbp1a, pbp2x, pbp2b	Drug target alteration	MIC or disk diffusion, PCR-based methods, DNA microarray-based	Levofloxacin, moxifloxacin, vancomycin
ESBL-producing Enterobacteriaceae^Citation23,Citation25–28	blaCTX-M, blaTEM, blaSHV, blaOXA‐10, blaOXA‐13 to 19	Enzymatic drug inactivation	ESBL gradient test, Combination disk diffusion test (CDT), Broth microdilution, Double disk synergy test (DDST), PCR-based methods, DNA microarray-based	Piperacillin/tazobactam, cefoperazone/sulbactam, oxycephalosporin, cefmetazole, cefminox, cefoxitin, ertapenem
Acquired AmpC β-lactamase-producing Enterobacteriaceae^Citation24,Citation26,Citation29,Citation30	blaCMY, blaFOX, blaMOX, blaLAT, blaACC, blaACT, blaMIR‐1, blaDHA	Enzymatic drug inactivation	inhibition of AmpC (cloxacillin or boronic acid derivatives), the Mast ‘AmpC Detection Disc Set’, the AmpC gradient test, PCR-based methods, DNA microarray-based	Ertapenem, imipenem/cilastatin, meropenem, panipenem/betamipron, cefepime
Carbapenemase-producing Enterobacteriaceae^Citation32,Citation33,Citation78	blaKPC, blaNDM, blaOXA, blaIMP, blaVIM	Enzymatic drug inactivation	Diffusion methods, combination disk, Carba NP test, CIM, Hodge test, DDS, Etest, PCR, DNA microarray	A combination of drugs is recommended. Available drugs include: polymyxin E (colistin), polymyxin B, ceftazidime-avibactam, fosfomycin, tigecycline, minocycline
Multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa^Citation41,Citation68–76	blaTEM, bla SHV, blaCTX-M, blaOXA, blaIMP, blaVIM, blaSIM, blaNDM, blaSPM, blaGIM, blaDIM, intI 1, intI 2, adeA, adeB, adeC, adeRS, adeIJK, abeM, abrp, gyrA/B, pmrA/pmrB/ mcr-1	Enzymatic drug inactivation, efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites	MIC determination, disk diffusion, Etest, PCR-based methods	A combination of drugs is recommended. Available drugs are as follow. Acinetobacter baumannii: polymyxin B Pseudomonas aeruginosa: Polymyxin E (colistin), cefoperazone/sulbactam + minocycline

Abbreviations: MIC, minimum inhibitory concentration; ESBL-producing, Extended-spectrum β-lactamase-producin.

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